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Rosuvastatin and Atorvastatin Are Ligands of the Human Constitutive Androstane Receptor/Retinoid X Receptor α Complex
Journal article   Open access   Peer reviewed

Rosuvastatin and Atorvastatin Are Ligands of the Human Constitutive Androstane Receptor/Retinoid X Receptor α Complex

Tadeja Režen, Mateja Hafner, Sandhya Kortagere, Sean Ekins, Vesna Hodnik and Damjana Rozman
Drug metabolism and disposition, v 45(8), pp 974-976
Aug 2017
DOI: https://doi.org/10.1124/dmd.117.075523
PMID: 28536098
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1124/dmd.117.075523View
Published, Version of Record (VoR)Maybe Open Access (Publisher Bronze),  Open

Abstract

Anticholesteremic Agents - metabolism Atorvastatin Calcium - metabolism Computer Simulation Hep G2 Cells Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism Ligands Protein Binding - physiology Receptors, Cytoplasmic and Nuclear - metabolism Retinoid X Receptor alpha - metabolism Rosuvastatin Calcium - metabolism
Statins are well known lipid lowering agents that inhibit the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. They also activate drug metabolism but their exact receptor-mediated action has not been proven so far. We tested whether atorvastatin and rosuvastatin are direct ligands of human constitutive androstane receptor (CAR). We measured binding activities of atorvastatin and rosuvastatin to the human constitutive androstane receptor/retinoid X receptor ligand-binding domain (CAR/RXR -LBD) heterodimer with surface plasmon resonance (SPR). Additionally, three-dimensional models of CAR/RXR -LBD were constructed by ligand-based and structure-based in silico modeling. Experiments and computational modeling show that atorvastatin and rosuvastatin bind to the human CAR/RXR -LBD heterodimer, suggesting both can modulate the activity of CAR through direct interaction with the LBD of this receptor. We confirm that atorvastatin and rosuvastatin are direct ligands of CAR. The clinical consequences of CAR activation by statins are in their potential drug-drug interactions, and changes in glucose and energy metabolism.

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Domestic collaboration
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Web of Science research areas
Pharmacology & Pharmacy
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